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PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2

Oncogene volume 27, pages 6571–6580 (2008)Cite this article

A Retraction to this article was published on 13 February 2017

A Corrigendum to this article was published on 04 July 2016

Abstract

p53 mutations occur frequently in human tumors. The low-molecular-weight compound PRIMA-1MET reactivates mutant p53, induces apoptosis in human tumor cells and inhibits tumor xenograft growth in vivo. Here, we show that PRIMA-1MET induces mutant p53-dependent mitochondria-mediated apoptosis through activation of caspase-2 with subsequent cytochrome c release and further activation of downstream caspase-9 and caspase-3. Inhibition of caspase-2 by a selective inhibitor and/or siRNA prevents cytochrome c release on PRIMA-1MET treatment and causes a significant reduction in PRIMA-1MET-induced cell death. Our findings highlight a chain of cellular events triggered by PRIMA-1MET that lead to apoptotic cell death. This should facilitate further development and optimization of efficient PRIMA-1MET-based anticancer drugs.

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Abbreviations

Δψm:

mitochondrial membrane potential

FACS:

fluorescence-activated cell sorting

G3PDH:

glyceraldehyde-3phosphate dehydrogenase

PI:

propidium iodide

fmk:

fluoromethyl ketone

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Acknowledgements

This study was supported by grants from the Swedish and Stockholm Cancer Societies, the Swedish Research Council, the EU 6th and 7th Framework Programs, and Karolinska Institutet. This publication reflects the author's views and not necessarily those of the EC partners. The information in this document is provided as is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at its sole risk and liability. The Community is not liable for any use that may be made of the information contained herein.

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Author notes

  1. H Stridh

    Present address: 3Current address: Amgen, Stockholm 169 27, Sweden.,

Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden

    J Shen, H Stridh & K G Wiman

  2. Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    H Vakifahmetoglu & B Zhivotovsky

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  1. J Shen
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  2. H Vakifahmetoglu
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  4. B Zhivotovsky
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  5. K G Wiman
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Corresponding author

Correspondence to K G Wiman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Shen, J., Vakifahmetoglu, H., Stridh, H. et al. PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene 27, 6571–6580 (2008). https://doi.org/10.1038/onc.2008.249

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